Unknown

Dataset Information

0

Preclinical development of T-cell receptor-engineered T-cell therapy targeting the 5T4 tumor antigen on renal cell carcinoma.


ABSTRACT: 5T4 (trophoblast glycoprotein, TPBG) is a transmembrane tumor antigen expressed on more than 90% of primary renal cell carcinomas (RCC) and a wide range of human carcinomas but not on most somatic adult tissues. The favorable expression pattern has encouraged the development and clinical testing of 5T4-targeted antibody and vaccine therapies. 5T4 also represents a compelling and unexplored target for T-cell receptor (TCR)-engineered T-cell therapy. Our group has previously isolated high-avidity CD8+ T-cell clones specific for an HLA-A2-restricted 5T4 epitope (residues 17-25; 5T4p17). In this report, targeted single-cell RNA sequencing was performed on 5T4p17-specific T-cell clones to sequence the highly variable complementarity-determining region 3 (CDR3) of T-cell receptor ? chain (TRA) and ? chain (TRB) genes. Full-length TRA and TRB sequences were cloned into lentiviral vectors and transduced into CD8+ T-cells from healthy donors. Redirected effector T-cell function against 5T4p17 was measured by cytotoxicity and cytokine release assays. Seven unique TRA-TRB pairs were identified. All seven TCRs exhibited high expression on CD8+ T-cells with transduction efficiencies from 59 to 89%. TCR-transduced CD8+ T-cells demonstrated redirected cytotoxicity and cytokine release in response to 5T4p17 on target-cells and killed 5T4+/HLA-A2+ kidney-, breast-, and colorectal-tumor cell lines as well as primary RCC tumor cells in vitro. TCR-transduced CD8+ T-cells also detected presentation of 5T4p17 in TAP1/2-deficient T2 target-cells. TCR-transduced T-cells redirected to recognize the 5T4p17 epitope from a broadly shared tumor antigen are of interest for future testing as a cellular immunotherapy strategy for HLA-A2+ subjects with 5T4+ tumors.

SUBMITTER: Xu Y 

PROVIDER: S-EPMC6877496 | BioStudies | 2019-01-01

REPOSITORIES: biostudies

Similar Datasets

2016-01-01 | S-EPMC4982452 | BioStudies
2020-01-01 | S-EPMC7500136 | BioStudies
2019-01-01 | S-EPMC6833194 | BioStudies
2018-01-01 | S-EPMC5748856 | BioStudies
2022-04-08 | GSE195956 | GEO
2010-01-01 | S-EPMC2912399 | BioStudies
2020-01-01 | S-EPMC7408051 | BioStudies
2018-01-01 | S-EPMC7368991 | BioStudies
1000-01-01 | S-EPMC2206586 | BioStudies
1000-01-01 | S-EPMC3666644 | BioStudies